In this resubmission, Project 5 of the original proposal has been deleted, but the study of the age-related changes in layer 1 of cerebral cortex has been retained and is now included in this Project. This Project will define the structural changes that occur with age in the central nervous system. By using middle aged monkeys we will determine when these changes first occur, and because all monkeys are behaviorally tested, we will relate structural changes to cognition. The study of layer 1 is retained because we have found that the age-related thinning and the loss of synapses from layer 1 is the most obvious change in the cortex, and in area 46 we have shown that these changes correlate with both age and cognitive decline. We need to know if these changes are ubiquitous, and so we propose to examine layer 1 in entorhinal cortex and in area 17 to ascertain if age produces similar changes in these cortices and if they also correlate with cognitive decline. We need to know if these changes are ubiquitous, and so we propose to examine layer 1 in entorhinal cortex in area 17 to ascertain if age produces similar changes in these cortices and if they also correlate with cognitive decline. Another major goal is to further pursue the breakdown of myelin sheaths we have shown to occur with age: we believe that this breakdown brings about cognitive decline through alterations in conduction rates, affecting timing in neuronal circuits. The two model systems we have chosen to examine myelin breakdown brings about cognitive decline through alterations in conduction rates, affecting timing in neuronal circuits.. The two model systems we have chosen to examine myelin sheaths, nerve fiber loss, and active phagocytosis undertaken by both astrocytes and microglial cells. We will also examine the splenium of the corpus callosum, the vertical nerve fiber bundles in area 46, the optic radiations, and the fornix, for additional information about age-related nerve fiber changes and loss with age. Our data on the myelin breakdown in the cerebral cortex and the splenium will be correlated state of the myelin sheaths whose composition is being examined in Project 2. Another aim is to use antibodies to label microglial cells and oligodendrocytes to determine how these neuroglial types respond to age changes in white matter. We will determine when microglial cells first become activated and whether some fiber pathways are more affected than others. For oligodendrocytes, it is intended to determine if they increase in frequency with age, in response to the breakdown of their myelin sheaths.